The present invention relates to a composition comprising a biocompatible polymer and specially adapted for forming at least part of a suppository. The composition preferably comprises a medicament.
CN 1109347 concerns a suppository made from a polyurethane sponge. The sponge in the shape of a suppository is dipped into a solution of the medicament to absorb it and is subsequently dried.
U.S. Pat. No. 4,292,300 relates to a non-dissolving, non-disintegrating slow-release suppository base consisting essentially of a linear polymer, such as methyl cellulose, and water in an amount of more than 35 parts by weight and less than 65 parts by weight of linear polymer. The linear polymers according to U.S. Pat. No. 4,292,300 can be distinguished from cross-linked polymers which swell, but do not dissolve in the presence of water and certain organic solvents. The linear polymers according to U.S. Pat. No. 4,292,300 have a high molecular weight, an affinity for water, and will dissolve in excess water, but in the relatively small amounts of water used in the formulation according to U.S. Pat. No. 4,292,300, a xe2x80x9cgelxe2x80x9d-like mass is formed. The linear polymers preferably resist biodegradation, or they are only slowly biodegradable. The polymers are capable of being extruded at ambient or near ambient temperatures, e.g. from 15xc2x0 C. to 40xc2x0 C., to give products with good strength and elasticity. They also have the ability to become instantaneously slippery when only slightly moistened and are therefore easily inserted into the anorectal or vaginal passage, this property is enhanced by the presence of the relatively large amounts of water in the formulations according to U.S. Pat. No. 4,292,300. Examples of linear polymers are methylcellulose, hydroxyproplymethylcellulose, hydroxymethylcellulose, polyvinyl alcohols, polyvinyl pyrrolidones, polyacrylamides, polyethylene oxides and certain modified starches. Typical average molecular weights vary between 100,000 and 300,000.
U.S. Pat. No. 4,405,883 relates to a non-dissolving, non-disintegrating, slow-release, shaped suppository consisting essentially of polyvinyl pyrrolidone, water, and a therapeutically effective amount of a water-soluble therapeutically active ingredient, wherein the water is present in an amount of more than 35 parts by weight wherein the suppository has flexibility and becomes slippery when moistened,
U.S. Pat. No. 5,330,427 relates to an improved suppository applicator which is a one-piece injection molded suppository applicator for ejecting medicament into a body cavity comprising a cylindrical main body portion having a distal end and a proximal end. The main body portion further comprises: an integral flexible chamber means at the distal end; a flexible junction means adjacent, integral to and at least partially the flexible chamber means; a plunger means adjacent and integral to the flexible chamber means; and a barrel stem; wherein the flexible junction means integrally joins the plunger means and flexible chamber means within the barrel stem.
U.S. Pat. No. 4,292,299 relates to a medical preparation composed of an adhesive layer comprising polymers which have adhesiveness to a wet mucous surface and swellability upon moistening and a nonadhesive layer which has no adhesiveness to a wet mucous surface and is water soluble or water disintegrable, with at least one of the layers made to contain a medicament. The medical preparation is administered by adhering to a wet mucous surface of the mucousal membrane and skin of men or animals, wherein exhibiting a property to release the medicament slowly extending over a long period of time to cure or prevent general or local diseases.
U.S. Pat. No. 4,404,296 relates to a polyol gel comprising i) 15-62 weight % (based on i)+ii)) of a high molecular weight covalently cross-linked polyurethane matrix; ii) 85-38 weight % (based on i)+ii)) of a liquid dispersing agent which is firmly bonded in the matrix by secondary valence forces; and optionally iii) fibers and/or additives and/or catalysts suitable for an isocyanate polyaddition reaction and/or active ingredients.
U.S. Pat. No. 5,411,737 relates to a slow release drug delivery device for the prolonged administration of topically active medicines which consists of a vehicle in which water is soluble. In the vehicle is dissolved a topically active drug formed into a stable organogel with a polymer matrix with a very low water absorbing capability. The organogel, in the presence of water or atmospheric water vapor, slowly imbibes such water into the vehicle and by doing so the vehicle becomes incompatible with the matrix and is slowly expelled therefrom. The vehicle dissolves the drug and the vehicle/drug combination is slowly pumped out of the polymeric matrix with substantially linear drug delivery occurring for periods in excess of 6 months. The drug delivery device may be used to administer drugs topically, such as a suppository or a subcutaneous implant.
U.S. Pat. No. 5,085,650 relates to a urethral suppository comprising i) a relatively long, relatively small diameter shaft, ii) a bulbous head extending from a rounded nose through a relatively gradually outwardly curving insertion surface having an axial length equaling about two thirds of the overall length of the head and a relatively sharply curving retention surface extending from the intersection with the insertion surface which is the maximum diameter of the head to an intersection with the shaft, the intersection between the retention surface and the insertion surface not comprising a sharp edge or corner, and iii) a conical tail including an outwardly tapered retaining surface extending from the shaft to a base having a diameter substantially greater than the maximum diameter of the bulbous head, wherein said shaft, head, and tail comprises predetermined dimensions and a unitary structure and are formed entirely from a medicament
U.S. Pat. No. 4,999,342 relates to a long lasting, viscous, adhesive contraceptive made from a quick melting suppository composition and comprising a mixture of a contraceptive effective amount of a spermicidal agent; a polymeric gum, such as a polysaccharide gum; a dispersing agent comprising silica; and a water miscible polymer suppository base, such as polyethylene glycol.
U.S. Pat. No. 4,765,978 relates to an antifungal vaginal suppository which contain cis-2-(1H-imidazolylmethyl)-3-(2xe2x80x2,6xe2x80x2-difluorobenzyloxy)-2,3-dihydro-5-fluo robenzo[b]thiophene as the antifungal agent, in a suppository base containing biocompatible polymers, a surfactant and an absorbent in a vegetable oil phase. The suppositories are substantive and provide a prolonged duration of effectiveness. The biocompatible polymer component of the suppository formulation comprises a combination of polyethylene and polyvinylpyrrolidione.
U.S. Pat. No. 5,750,100 relates to a sustained releasable parenteral pharmaceutical preparation in which a great release of a physiologically active peptide or protein in an early stage of the administration is suppressed and the peptide or protein can be released for a longer period. The sustained releasable parenteral pharmaceutical preparation of the present invention comprises a matrix comprising a physiologically active peptide or protein and a polyglycerol diester of a saturated fatty acid. The matrix may be in a pillar, granular or other form.
U.S. Pat. No. 4,259,314 relates to a controlled release, dry pharmaceutical composition containing a dry carrier comprised of 80 to 95% of hydroxypropyl methylcellulose and 20 to 5% of hydroxypropyl cellulose. The carrier is dried to a moisture content of not more than 1%. If the pharmaceutical composition is compressed under low pressure, a troche capable of being sucked or used in the mouth can be prepared, and a controlled release of the active therapeutic agent, which is mucousally absorbed into the blood stream is achieved. If higher pressures are used to compress the pharmaceutical material a harder and longer-lasting pharmaceutical composition can be prepared suitable for rectal or vaginal application or suitable for swallowing in the form of a tablet.
U.S. Pat. No. 4,786,502 relates to a lipid-containing, molded pharmaceutical composition comprising i) from about 10% to about 50% of a lipid material having a melting point of from about 26xc2x0 C. to about 37xc2x0 C., ii) from about 10% to about 50% of a particulate dispersant material, iii) from about 0.1% to about 3% of an emulsifier, and iv) a safe and effective amount of a pharmaceutically active material, wherein preferably the measured. Viscosity of the composition is less than about 10,000 cps at about 40xc2x0 C.
U.S. Pat. No. 5,529,782 relates to a dissolvable element containing an agent material that is used for local administration of an agent material in an internal body area. The dissolvable element is made of a dissolvable polymer material and/or complex carbohydrate material which are food grade materials and have selected dissolving properties, such that it remains in substantially solid form before use, and dissolves due to human body temperatures and moisture during use to release the agent material in a desired timed release and dosage.
U.S. Pat. No. 5,859,048 relates to pharmaceutics for rectal administration in which at least either a pharmacologically active ingredient or a mucousal absorption enhancer is caused to form a complex with a high molecular compound which is soluble in water at pH 5 or higher. The ingredient and the enhancer are uniformly dispersed in a fatty suppository base.
U.S. Pat. No. 5,436,009 relates to a sustained release suppository comprising in a usual *suppository base, such as a fat having a melting range of from 29xc2x0 C. to 38xc2x0 C., i) a water-soluble therapeutically active substance, ii) a physiologically acceptable organic substance that is swellable in contact with water, such as hydroxypropylmethylcellulose, and iii) a hydrophobic silicium dioxide.
U.S. Pat. No. 4,853,211 relates to an effervescent vaginal suppository composition containing a stabilizer, such as anhydrous sodium sulfate, anhydrous silica gel, dried magnesium silicate, dried aluminum silicate, dried calcium carboxymethylcellulose, dried microcrystalline cellulose, dried starch and dried calcium phosphate, or mixtures thereof, preferably in an amount of from 0.1 to 20% based on the weight of said effervescent vaginal suppository composition.
U.S. Pat. No. 4,698,359 relates to a medicated suppository for use in the vaginal or rectal cavity comprising a medicament, a mixture of triglycerides of fatty acids, a gel forming agent and a gel dispersing agent.
U.S. Pat. No. 4,402,692 relates to a medicament capsule encapsulating an effective ingredient. The medicament capsule is formed of a hard capsule shell made of a mixed ester of a cellulose ether, e.g. alkyl-, hydroxyalkyl- and hydroxyalkyl alkylcelluloses, esterified with aliphatic monacyl groups and acidic succinyl groups. When the capsule is inserted into the rectum, the capsule shell is disintegrated and the rectally absorbable effective ingredient is released into the rectum.
The present invention in one preferred aspect relates to a suppository for administration of at least one bioactive substance, said suppository comprising
i) a polymer composition comprising at least one biocompatible polymer, wherein the biocompatible polymer is essentially non-biodegradable; and
ii) a controlled release formulation for controlled release of said at least one bioactive substance, said formulation comprises at least one first polymer and/or at least one second polymer, wherein the melting point of said at least one first polymer is lower than the melting point of said at least one second polymer; and
wherein preferably, the suppository essentially does not swell when contacted with an aqueous fluid.
The polymer composition according to the present invention comprises a biocompatible polymer that essentially does not swell when being contacted by moisture. The biocompatible polymer is also essentially non-biodegradable and is thus essentially not degraded during use when forming part of e.g. a suppository used in therapeutical methods including surgery.
At least part of the polymer composition comprising the biocompatible polymer preferably further comprises a plurality of interlinked, open cells that are accessible to mucousal membrane fluids and capable of containing such aqueous fluids. The contacting of the polymer composition with an aqueous fluid such as moisture secreted from the mucousal membrane under practical circumstances preferably results in essentially no fluid entering the open, accessible cells. The term xe2x80x9cessentially no fluidxe2x80x9d will be understood to mean an amount of fluid that results in no dehydration, or at least essentially no dehydration of the mucousal membrane in contact with the suppository according to the invention, while still allowing the fluid to contact a medicament comprised in open, accessible cells, optionally in encapsulated form, wherein the contacting of the fluid and the medicament, or the encapsulation thereof, results in the delivery of the medicament to the mucousal membrane in a pharmaceutically active amount. Dehydration of a mucousal membrane is evident from clear signs of irritatation of the mucousal membrane tissue. Irritation is routinely diagnosed by a medical practitioner, or by the individual sensing an itching or developing a rash in a body cavity region.
The invention thus in one embodiment pertains to a suppository comprising a polymer composition having a permeability for aqueous fluids, including body fluids, that resultsxe2x80x94under practical circumstancesxe2x80x94in entry of such body fluids into a plurality of open cells comprised in the polymer composition essentially without dehydration of mucousal membrane tissue contacting the suppository.
Any biocompatible polymer that is essentially not degraded during use and essentially does not swell when being contacted by moisture can be used in accordance with the present invention. The terms xe2x80x9cnot degradedxe2x80x9d and xe2x80x9cdoes not swellxe2x80x9d shall in the following be used within the meaning xe2x80x9cessentially not degradedxe2x80x9d and xe2x80x9cessentially does not swellxe2x80x9d, respectively, as defined herein below.
The non-biodegradable polymer provides the polymer composition with a desirable degree of flexibility and ensures that a firm contact is established between the surface of the suppository and e.g. a mucousal membrane in a body cavity of an individual wherein the suppository is positioned. Preferably, the controlled release formulation has a softening point, so that the suppository is essentially rigid at room temperature, whereas the suppository is essentially soft or less rigid at body temperature. This can be measured by e.g. measuring the rigidity of the suppository by any state of the art method.
The suppository preferably comprises a bioactive substance including a medicament capable of being controllably released in the body cavity in question. As the suppository is not degraded during use it will provide a prolonged release of a medicament in the local environment. With which the suppository is in operable contact.
The suppositories according to the present invention in one embodiment solves the problem of how to provide medicaments to a local environment without generatingxe2x80x94at essentially the same timexe2x80x94a systemic effect caused by caused by solvation, melting or otherwise, of the vehicle acing as a carrier of the medicament. This technical effect is in sharp contrast to state of the art suppositories made of fat-like substances that are degraded during use, typically through a process of melting or dissolving the carrier matrix.
The degradation of suppositories has the effect that administration of the medicament is not targeted to a local environment over a prolonged period of time. As a local environment is not targeted exclusively with state of the art suppositories, the medicament is taken up by the organism and exerts a systemic effect in the entire body.
The present invention in one preferred embodiment is aimed at ensuring a direct delivery of a medicament to a local environment while essentially preventing the medicament from being taken up by the body and thereby exerting a systemic effect. Furthermore, the biocompatible polymer does not melt or disintegrate, so that the medicament preferably is essentially retaining in a local environment. The present invention thus provides a means for sustained release administration of a medicament to a predetermined, local environment without essentially generating any systemic effects. However, in other embodiments of the present invention a systemic effect may be desirable.
Hence, the advantages of suppositories according to the present invention are:
i) physiological compliance
ii) fast adjustment to the shape of any body cavity
iii) large contact surface between suppository and mucosal membrane
iv) increased transport and mobility of the bioactive substance
v) water solubility of the bioactive substance
vi) local administration of the bioactive substance
vii) promotes wound healing